Cholestasis is defined as the impairment or cessation of bile flow and occurs in a variety of human liver diseases. Although there are various pathogenic causes of cholestasis, hepatocellular injury and associated liver dysfunction commonly result (Trauner et al. N. Engl. J. Med. 1998 339:1217-27). Ursodeoxycholic acid (UDCA) is currently the only established drug for the treatment of a variety of cholestatic liver diseases, such as primary biliary cirrhosis, primary sclerosing cholangitis, cystic fibrosis, and intrahepatic cholestasis of pregnancy (Kumar, D. and Tnadon, R. K. J. Gastroenterol. Hepatol. 2001 16:3-14; Beuers et al. Hepatology 1998 28:1449-53; Poupon, R. and Poupon, R. E. Pharmacol. Ther. 1995 66:1-15). The molecular mechanisms underlying the therapeutic benefits of UDCA are not fully understood but may be a result of immunomodulatory, antiapoptotic, cytoprotective and choleretic effects (Beuers et al. Hepatology 1998 28:1449-53).
Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily of ligand activated transcription factors (Lu et al. J. Biol. Chem. 2001 17:17). FXR is reported to bind and be activated by a variety of naturally occurring bile acids, including the primary bile acid chenodeoxycholic acid and its taurine and glycine conjugates (Makishima et al. Science 1999 284:1362-5; Parks et al. Science 1999 284:1365-8; and Wang et al. Mol. Cell. 1999 3:543-53). A number of recent studies have implicated FXR in the regulation of genes encoding proteins involved in the biosynthesis and transport of bile acids (Sinal et al. Cell 2000 102:731-44; Lu et al. Mol. Cell 2000 6:507-15; Goodwin et al. Mol. Cell. 2000 6:517-26; Grober et al. J. Biol. Chem. 1999 274:29749-54).
Using a potent selective FXR ligand, it has now been found that FXR ligands are hepatoprotective in bile duct-ligated (BDL) rats, a well-characterized model of extrahepatic cholestasis. These data are indicative of FXR ligands being effective in the treatment of cholestatic liver disease.